The inhaled p38 α/β mitogen-activated protein kinase inhibitor PF-03715455 is an example of "inhalation by design" pharmacologically active substance which maximize pulmonary residence and local efficacy, demonstrating a slow absorption rate and a prolonged pulmonary retention. However, for dry powder inhalers dissolution in the pulmonary lining fluid can become the rate-limiting step for drug absorption and bioavailability. The present study investigated the relationship between in vitro dissolution and in vivo pulmonary pharmacokinetics of two micronized PF-03715455 powders with different solid state, amorphous vs pseudo-crystalline. Powders were characterized by scanning electron microscopy and aerosol performance analysis using the PreciseInhale® coupled with cascade impactor. Dissolution studies were performed with RespiCell® apparatus directly on the respirable fraction obtained from PreciseInhale® aerosolization. Pulmonary pharmacokinetics were then evaluated following intratracheal administration in rats. Both formulations exhibited comparable aerodynamic properties. However, marked differences were observed in dissolution behavior. After 8 h, only 3% of the amorphous powder and 0.4% of the pseudo-crystalline powder dissolved, confirming the extremely low aqueous solubility of the compound. These differences strongly influenced in vivo performance. The amorphous formulation showed enhanced systemic exposure and faster decline of lung concentrations, whereas the pseudo-crystalline powder exhibited prolonged pulmonary retention with minimal plasma exposure. The results demonstrated a clear correlation between dissolution rate and pulmonary absorption kinetics. Overall, the study highlights the critical role of dissolution testing in predicting the in vivo behavior of poorly soluble inhaled drugs and supports the use of biologically relevant in vitro dissolution methods during early-stage formulation development.
Inhaled product dissolution as a predictive tool of drug bioavailability: a p38 MAPK inhibitor case study using Respicell® dissolution apparatus / Patterlini, V., Marenghi, G., Fioni, A., Trevisi, G., Mazzeo, P.P., Quarta, E., Buttini, F., Sonvico, F.. - In: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES. - ISSN 0928-0987. - 225:(2026). [10.1016/j.ejps.2026.107610]
Inhaled product dissolution as a predictive tool of drug bioavailability: a p38 MAPK inhibitor case study using Respicell® dissolution apparatus
Patterlini V.Writing – Original Draft Preparation
;Marenghi G.Investigation
;Trevisi G.Methodology
;Mazzeo P. P.Methodology
;Quarta E.Resources
;Buttini F.Supervision
;Sonvico F.
Writing – Review & Editing
2026-01-01
Abstract
The inhaled p38 α/β mitogen-activated protein kinase inhibitor PF-03715455 is an example of "inhalation by design" pharmacologically active substance which maximize pulmonary residence and local efficacy, demonstrating a slow absorption rate and a prolonged pulmonary retention. However, for dry powder inhalers dissolution in the pulmonary lining fluid can become the rate-limiting step for drug absorption and bioavailability. The present study investigated the relationship between in vitro dissolution and in vivo pulmonary pharmacokinetics of two micronized PF-03715455 powders with different solid state, amorphous vs pseudo-crystalline. Powders were characterized by scanning electron microscopy and aerosol performance analysis using the PreciseInhale® coupled with cascade impactor. Dissolution studies were performed with RespiCell® apparatus directly on the respirable fraction obtained from PreciseInhale® aerosolization. Pulmonary pharmacokinetics were then evaluated following intratracheal administration in rats. Both formulations exhibited comparable aerodynamic properties. However, marked differences were observed in dissolution behavior. After 8 h, only 3% of the amorphous powder and 0.4% of the pseudo-crystalline powder dissolved, confirming the extremely low aqueous solubility of the compound. These differences strongly influenced in vivo performance. The amorphous formulation showed enhanced systemic exposure and faster decline of lung concentrations, whereas the pseudo-crystalline powder exhibited prolonged pulmonary retention with minimal plasma exposure. The results demonstrated a clear correlation between dissolution rate and pulmonary absorption kinetics. Overall, the study highlights the critical role of dissolution testing in predicting the in vivo behavior of poorly soluble inhaled drugs and supports the use of biologically relevant in vitro dissolution methods during early-stage formulation development.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
